Cyclic polypeptides

Therapeutic Function Antitubercular Chemical Name Cyclic polypeptide antibiotic Common Name Caprolin Structural Formula ... 

Cyclosporine is a cyclic polypeptide immunosuppressant typically used to prevent organ rejection in transplant patients. Its use is restricted to patients with fulminant or refractory symptoms in patients with active IBD. Significant toxicides associated with cyclosporine are nephrotoxicity, risk of infection, seizures, hypertension, and liver function test abnormalities.1,13,14... 

Macrocyclic compounds with ion-chelating properties occur naturally and often function as ionophores, translocating ions across biological membranes many of these compounds are small cyclic polypeptides. Some natural carboxylic polyethers are selective for Li+ and are, therefore, ionophores for Li+. Monensin, shown in Figure Id, is a natural ionophore for Na+ but it will also complex with Li+ and it has been shown to mediate the transport of Li+ across phospholipid bilayers [21]. It has been proposed that synthetic Li+-specific ionophores have a potential role as adjuvants in lithium therapy, the aim being to reduce the amount of... 

Natural products derived from amino acids form a broad and divergent group, including simple amino acid derivatives, alkaloids, and small, often cyclic, polypeptides. Simple amino acid derivatives, which are not uncommon in algae, are often oxidation or rearrangement products of one of the 20 common amino acids. Alkaloids and polypeptides are more complex in their structural modifications. 

Dactinomycin Dactinomycin, 2-amino-l,9-bis-(2,9-diisopropyl-6,10,13-trimethyl-l,4,8,ll,14-pentaoxo-7-oxa-3,10,13-17a-tetraaza-5-bicyclo[14.3.0]nonadecylcarbamoyl)-4,6-dimethyl-3//-phenoxazin-3-one (30.3.1), is one of the first antibiotics isolated from a liquid culture of microorganisms of the family Streptomyces parvulus [80-87]. It is a chromonopeptide with a phenoxazine ring and two cyclic polypeptides joined to the carboxyl group at position 2 and 9 of the phenoxazine ring. 

Cyclosporine is a highly stable 11-amino acid cyclic polypeptide. The molecule is very lipophilic and essentially is not soluble in water. It can be administered intravenously, orally, or by injection. 

Mecfianism of Action A cyclic polypeptide antimicrobial but the mechanism of action is not well understood. Therapeutic Effect Suppresses mycobacterial multiplication. Pharmacokinetics Not well absorbed from the GI tract. Undergoes little metabolism. Primarily excreted unchanged in urine. Haif-iife 4-6 hr (half-life is increased with impaired renal function). 

Mectianism of Action A cyclic polypeptide that inhibits both cellular and humoral immune responses by inhibiting interleukin-2, a proliferative factor needed for T-cell ac-tivityT herapeuticEffect Prevenfs organ rejecfion and relieves sympfoms of psoriasis and arfhrifis. 

It is a cyclic polypeptide with 11 amino acids. It selectively inhibits T-lymphocytes proliferation, IL-2 and other cytokine production. It is the most effective drug for prevention and treatment of graft rejection reaction. It is used in cardiac, hepatic, renal, bone marrow transplantation and as second line drug in rheumatoid arthritis, inflammatory bowel disease, dermato-myositis, bronchial asthma and certain other autoimmune diseases. 

In addition to improving drug absorption, permeation enhancers that form mixed micelles with peptides or proteins may also provide protection against metabolic processes, including protease-dependent inactivation, efflux transport, and protein denaturation, all of which could lead to reduced bioavailabUity. A permeation enhancer that may also inhibit some competing metabolic processes could greatly improve the poor and inconsistent bioavailabiUty of some short and cyclic polypeptides such as cyclosporine (11 aa cyclic peptide) (Figure 13.11). 

Virginiamycin is a mixture of two components designated Mi and Si, which are both cyclic polypeptides. It is soluble in methanol, ethanol, acetic acid, ethyl acetate, acetone, chloroform, and benzene but is practically insoluble in water and dilute acid. It also dissolves in alkalis but is rapidly deactivated. 

The synthesis of Berninamycinic acid (605), a degradation product of the cyclic polypeptide antibiotic berninamycin, begins with an instructive differentiation of reactivity of the unsymmetrical pyridine diamide 601 (Scheme 178) [84TL(25)2127]. Metalation of 601 with 4.2 equiv. of A-BuLi followed by injection of 2.2 equiv. of the shown isothiocyanate afforded... 

Cyclic polypeptides, or polypeptides devoid of terminal amino groups are amongst the products of, at least, some polymerisations initiated by aprotic bases. 

Capreomycin is a mixture of cyclic polypeptides obtained from cultures of Streptomyces capreolus, and contains about 90% of capreomycins I, principally capreomycin IB (Figure 7.21). The capreomycin structures incorporate an L-capreomycidine moiety derived by cyclization of L-arginine, and three molecules of 2,3-diaminopropionic acid (Dap), which originate from serine via dehydroalanine. This antibiotic is given intramuscularly to treat tuberculosis patients who do not respond to first-line drugs, or where patients are sensitive to... 

Cyclosporin A, a fungal metabolite, is a cyclic polypeptide that consists of 11 amino acids. It has a biologic half-life of 4 to 6 h and displays a preferential T cell cytotoxic property, in that it inhibits the factors that stimulate T lymphocyte proliferation. Cyclosporin A has been used as the sole immunosuppressant (without prednisone or other drugs) for cadaveric transplants of the kidney, pancreas, and liver. Cyclosporin A has been observed to cause reversible hepatic toxicity and nephrotoxicity. 

A lipophilic tripeptide, janolusimide (342), was isolated from the Mediterranean nudibranch Janolus cristatus and was found to be toxic to mice (260). From the Swedish sponge Geodia baretti barettin, a cyclic polypeptide, was isolated and found to show inhibiting activity on electrically induced contractions of isolated guinea pig ileum (261). Barettin is composed of dehydro-6-bromotryptophan and proline. The initial proposed... 

G. Fong and B. T. Kho, Improved HPLC of cyclic polypeptide antibiotics-polymixins B- and its application to assays of pharmaceutical formulations, J. Liquid Chromatogr., 2 957 (1979). 

Caspofungin is a cyclic polypeptide that inhibits synthesis of the fungal cell wall. It can be used in systemic mycoses due to as-pergillus fungi when amphotericin B or itroconazole cannot be employed. It is given by infusion and causes various adverse effects. 

One of the aspects of structural complexity in biomolecules is that of stereochemistry. To the increase in stereochemical complexity when going to larger biomolecules correspond new stereochemical features and properties. Thus, the concepts of cycloenantiomerism, cyclodiastereoisomerism and cyclostereoisomerism have been introduced by Prelog and collaborators [118-120] to describe stereochemical features of cyclic molecules displaying 2n centers of chirality, e.g., cyclic polypeptides. 

Figure 15. Conversion of procarboxypeptidase A to carboxypeptidase A by trypsin (151). The subunits are not cyclic polypeptides. ATEEase and HPLAase represents activities of activated subunits I and II on acetyl-1-tyrosine ethyl ester and hippuryl phenyllactic acid, respectively.

Cyclospasmol cyclandelate. cyclosporin [ban] (ciclosporin [inn.jan] cyclosporine [usan] cyclosporin A Neoral Sandimmune ) is a cyclic polypeptide ANTIBIOTIC, possessing IMMUNOSUPPRESSIVE properties (with a specific action on T-lymphocytes). It also has ANTIFUNGAL activity and can be used clinically as an immunosuppressant after transplant surgery, and to treat severe autoimmune diseases including rheumatoid arthritis, cyclosporin A cyclosporine, cyclothiazide [ban. inn. usan] is a (thiazide) diuretic which can be used in ANTIHYPERTENSIVE therapy, cyclovalone [inn] (DVC) is a cyclohexanone, a choleretic... 

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